Basic & Clinical Pharmacology & Toxicology, 2015, 117, 280–285 Doi: 10.1111/bcpt.

12401

Levothyroxine Poisoning – Symptoms and Clinical Outcome

Birgitte Nygaard1,2, Eva A. Saedder3, Kim Dalhoff1, Mette Wikkelsoe1 and Gesche J€
urgens1,4
1
Department of Clinical Pharmacology and Toxicology, Copenhagen University Hospital, Bispebjerg, Denmark, 2Department of Geriatrics,
Copenhagen University Hospital, Bispebjerg, Denmark, 3Department of Pharmacology, Aarhus University Hospital, Aarhus, Denmark and 4Clinical
Pharmacological Unit, Roskilde University Hospital, Roskilde, Denmark
(Received 21 January 2015; Accepted 12 March 2015)

Abstract: Levothyroxine (LT), T4, poisoning is rarely associated with a severe outcome. However, cases with significant compli-
cations have been reported. The aim of this study was to identify factors associated with symptoms of poisoning including late-
onset symptoms. All enquiries to the Danish Poison Information Centre (DPIC) concerning LT poisoning between March 2007
and September 2012 were reviewed and the following parameters were recorded: age, dose, time from ingestion, multiple drug
intake and symptoms. To evaluate the frequency of late-onset symptoms, a subgroup of patients without initial symptoms were
contacted. A total of 181 patients were registered (112 children). Ingested LT dose ranged from 10 to 9000 mcg (median 275
mcg). A total of 29 of 181 (16%) patients were symptomatic at the time of enquiry, and there was no difference in ingested LT
dose between asymptomatic and symptomatic patients, neither in children nor in adults (age 16–92 years) (p < 0.68 and
p < 0.47, respectively). In total, 153 of 181 (85%) patients did not have symptoms of poisoning at the time of enquiry; however,
in 9 of 21 (43%) patients, we were able to contact, late-onset symptoms existed. In none of the cases, hospital contact was
needed and there were no reports of long-term sequelae. Acute LT poisoning often follows a benign course. The occurrence of
symptoms appears not to be dose dependent. Late-onset symptoms seem to be common. However, all symptoms resolved sponta-
neously without need of medical care.

When and how to treat levothyroxine (LT), T4, poisoning is
controversial and the risk of exposure weighted against gastro-
intestinal decontamination (GID) has been discussed [1]. The
initial lack of symptoms, coupled with widely varying individ-
ual clinical responses, makes it difficult to evaluate the effec-
tiveness of medical treatment in patients with acute LT
poisoning [2]. The benign clinical course of even massive
overdoses is often emphasized [3–6]. However, severe symp-
toms such as seizures in children [7,8] and malignant hyper-
thermia, arrhythmia and coma in adults have been reported
[9,10].
Despite higher mean LT and triiodothyronine (T3) levels in
children compared with adults, serious symptoms are less fre-
quently seen in children [11]. The apparent increased tolerance
to LT might be related to the increased metabolic capacity in
the liver during childhood, except in the neonatal period [12].
The risk of late-onset symptoms and the fact that LT poi-
soning in some cases has been associated with severe outcome
make it difficult to prepare general clinical guidelines, for
example in relation to a safe clinical observation level. Defin-
ing a specific ‘population at risk’ is important. Today’s prac-
tice in general is long-term observation regardless of patient
age.
The main objective of this study was to investigate acute
LT poisoning by evaluating the relation between ingested LT
dose, symptoms (severity) and age. We also investigated
Author for correspondence: Birgitte Nygaard, Department of Clinical
Pharmacology and Toxicology, Copenhagen University Hospital, Bis-
pebjerg Bakke 23, 2400 Copenhagen, Denmark (e-mail nygaardbirgit
ten@gmail.com).
late-onset symptoms, the influence of multiple drug ingestion
and GID on clinical outcome. Furthermore, some studies have
indicated a rather strong association between hyperthyroidism
and mortality [13,14], and that duration of hyperthyroidism
correlates with all-cause mortality and risk of hip fracture
[15,16]. Chronic LT poisoning was therefore also briefly
discussed.
Materials and Methods
All enquiries to the Danish Poison Information Centre (DPIC) between
March 2007 and September 2012 concerning LT poisoning were
reviewed – both single and multiple drug exposures. The study was
approved by the Danish Data Protection Agency (reference number:
BBH-2012-07). Data were extracted by two independent investigators.
Descriptive data included age (children defined as ≤15 years), gen-
der, cause of ingestion (intended/unintended), concomitant drugs, dose,
time between ingestion and contact to the DPIC, initiated treatment
and symptoms. Symptoms were categorized according to the ICH-
E2A guidelines by the European Medicines Agency (EMA) into seri-
ous or non-serious adverse reactions [17].
All patients (or their parents), who were asymptomatic at the initial
contact to the DPIC, were contacted by telephone and interviewed to
evaluate the frequency of late-onset symptoms. A structured question-
naire was used. Development of LT-related adverse reactions in the
period of 0–2 weeks after the ingestion was explored (Appendix).
Further, we performed a literature review concerning LT poisoning
in children. The PubMed database was searched using the terms ‘Lev-
othyroxine’, ‘Thyroxine’, ‘overdose’, ‘intoxication’ and ‘ingestion’.
The search was performed in September 2012 and limited to human
data presented in English. The selection of relevant articles was based
on an initial screening of the title and abstract and subsequent assess-
ment of the full article and performed by only one reviewer. Full-text
articles were hand-searched for further references.

© 2015 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
 LEVOTHYROXINE POISONING 281

For further risk assessment, a review of the GlaxoSmithKline safety
database (GSK safety database) between November 2002 and Febru-
ary 2012 concerning LT ingestion in children (≤ 14 years) was
performed.
Statistical analyses were performed in SAS JMP 9.02, SAS Cary,
NC 27513-2414, USA. Differences between groups were assessed
using chi-square test for categorical variables. A p-value<0.05 was
considered statistically significant.
(43%) (≤15 years) described tremor, diaphoresis, hyperactivity,
insomnia, tachycardia, fever and headache. They had ingested
LT (as a single drug) in the dose range of 300–15000 mcg, and
their symptoms started and ended within 24 hr. None of the
cases resulted in contact to the healthcare system or in serious
outcomes.

Review of the literature.

Results The systematic review of the literature identified 20 cases and
Enquiries from DPIC. case series describing acute LT poisoning in children (table 3).
Between March 2007 and September 2012, 181 cases of LT One case described a 13-year-old boy with primary hypothy-
ingestion were registered at DPIC. The most frequent cause roidism and prescribed daily intake of 100 mcg with LT.
was unintended ingestion due to play (53.9%), all children Ingestion of 9900 mcg resulted in elevated temperature
younger than 6 years old. The secondary cause was suicide (37.5°), mild tremor of hands and mild anxiety [18]. Only two
attempt (24.7%), all adolescents or adults (≥14 years). cases resulted in serious outcome (e.g. seizure). One healthy
Children younger than 5 years had the highest prevalence child aged 2.5 years ingested 18,000 mcg LT [7]. The other
of registered overdose. Ingested LT dose ranged from 10 to child aged 3.5 years ingested 3600 mcg LT [8]. No deaths
9000 mcg (median 275 mcg). Time from ingestion to DPIC were described.
contact ranged from 1 min. to 28 days (median 1 hr). Results
are outlined in table 1. Review of the GlaxoSmithKline safety database.
A total of 29 of 181 (16%) patients described symptoms at A review of the GSK safety database identified 47 cases (all
the time of enquiry (table 2). Adolescents and adults (age younger than 14 years) involved in accidental LT exposure/
16–92 years) were over-represented compared with children overdose. Cases were based on literature search and reports
(p < 0.0001), while there was no statistical difference from the consumers, physicians and other health professionals
in ingested LT dose between symptomatic and asymptomatic in the following countries: Argentina, Brazil, India, Israel,
in children or adolescents/adults (p < 0.68 and p < 0.47, Germany, United Kingdom, United States, Switzerland, Spain
respectively). and Canada. Symptoms were described in 10 (21%) cases and
In total, 53 of 181 (29%) patients had ingested multiple were as follows: tachycardia, agitation, hyperhidrosis, anxiety,
drugs and they had more frequent symptoms than patients vomiting, dizziness, insomnia, tremor, pyrexia, hyperactivity,
who had only ingested LT (p < 0.0001). In 172 of 181 (95%), diarrhoea, irritability, decreased appetite, flushing. A few
patient information concerning GID was described. In 34 of patients reported manifestations in skin such as oral mucosal
172 (20%) patients, GID was initiated prior to DPIC contact. discolouration, cutaneous lichenoid eruption, skin exfoliation
Patients treated with GID were not over-represented among and alopecia. The exposure range in the 10 symptomatic chil-
the asymptomatic patients (p < 0.89). dren was 100–9900 mcg versus 25–9600 mcg in asymptom-
A total of 153 of 181 (85%) patients had no symptoms of poi- atic children [19]. One child had taken other medications
soning at the time DPIC was contacted. We were only able to (ferrous sulphate, multivitamins) and developed symptoms.
trace 21 of 181 (12%) patients for follow-up, and nine of 21 Overall, seven children received LT for hypothyroidism. Five
Table 1.
Levothyroxine ingestion/intoxication registered at the Danish Poison Information Centre March 2007 to September 2012.
Age (years) ≤5 06–12 13–19 ≥20
No of individuals registered, n (%) 109 (60) 3 (2) 13 (7) 56 (31)
Sex (female), n(%) 51 (47) 2 (67) 11 (85) 50 (89)
Cause, n (%)
Intended ingestion
Abuse 0 0 0 3 (5)
Suicidal attempt 0 0 9 (69) 35 (63)
Unintended ingestion
Play 98 (90) 1 (33) 0 0
Accident 10 (9) 2 (67) 4 (31) 15 (27)
Unknown 1 (1) 0 0 3 (5)
Multiple drug ingestion, n (%) 8 (7) 0 4 (31) 45 (80)
LT dose ingested (mcg), 200 (100–600;50–4000) 150 (100–600;100–600) 400 (150–1100;10–1250) 500 (200–3938;50–9000)
median (IQR; Range)
Time since ingestion (h), 0.5 (0.25–1.4;0.01–96) 2 (0.5–3;0.5–3) 2.5 (1–5.5;0.2–48) 2.25 (1–5;0.2–672)
median (IQR; Range)
Individuals with symptoms, n (%) 3 (3) 0 3 (23) 23 (41)
n, number of individuals; mcg, microgram; IQR, interquartile range; h, hour.

© 2015 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
282 BIRGITTE NYGAARD ET AL.

Table 2.
Individuals registered with levothyroxine ingestion at the Danish Poison Information Centre with symptoms according to serious and non-serious
adverse reactions.
Case Age (y) Co-ingested drugs Serious adverse reactions Non-serious adverse reactions Treatment initiated
1 2.5 None Severe agitation Mild hyperactivity and mild Aspiration+charcoal
tachycardia
2 1.66 None Confusion Mild tremor, mild tachycardia, Not specified
dyspnoea
3 15 None Mild tachycardia None
4 49 None Psychotic Mild tremor, nausea, vomiting, Charcoal
hot flushes
5 36 None Restlessness None
6 ≤1 None Headache None
7 20 None None
8 70 None Severe hypertension None
1 30 Tramadol, amitriptyline Unconscious, severe None
hypotension
2 92 Isosorbiddinitrat, digoxin, Severe hypotension Dizziness, mild tachycardia None
metoprolol, oxycodone
3 48 Duloxetine Bradykardia, severe Vomiting None
hypotension
4 37 Ibuprofen Increased temperature, None
diarrhoea,
restlessness, mild
tachycardia
5 57 Quetiapine Consciousness affected None
6 21 Lorazepam, zopiclone Consciousness affected None
7 58 Nitrazepam, lamotrigine, citalopram Consciousness affected None
8 17 Chlorprothixen, lamotrigine Agitation None
9 21 Amlodipine, losartan Consciousness affected None
10 35 Gemcitabine, lamotrigine, pregabalin Consciousness affected None
11 27 Mild tachycardia None
12 32 Venlafaxine, aripiprazole, olanzapine Consciousness affected None
13 62 Mirtazepine, atenolol, simvastatin Confusion None
14 44 Alprazolam Consciousness affected None
15 55 Oxazepam, levomepromazine, QT prolongation, seizure Vomiting
lercanidipine, duloxetine
16 41 Lamotrigine, sertraline, chlorprothixen, Unconscious None
zopiclone, quetiapine, lithium
17 60 Chlorprothixen, orphenadrine, Severe agitation None
clonazepam
18 38 Ibuprofen, omeprazol, paracetamol Vomiting Charcoal
19 19 Citalopram Restlessness, flushing Aspiration+charcoal
20 27 Paracetamol Mild tachycardia Charcoal
21 1.5 Not specified Restlessness None
y, years. Serious adverse reactions: severe agitation, confusion, psychosis, unconsciousness, consciousness affected, severe hypertension (systolic
blood pressure >180 or/and diastolic blood pressure >110 mmHg), QT prolongation, bradycardia (<50 beat/min.) and hypotension (<100 mmHg).
Non-serious adverse reactions: mild hyperactivity, mild tachycardia (<120 per minute), mild tremor, dyspnoea, nausea, vomiting, hot flushes /flush-
ing, restlessness, headache, dizziness, increased body temperature and diarrhoea.

of these (71%) were symptomatic after accidental exposure/
overdose.
Discussion
The main objective of this study was to investigate risk fac-
tors for the development of immediate and delayed toxicity
after LT poisoning.
In accordance with previous reports from poison informa-
tion centres, we found that young children had the highest
prevalence of LT overdose [20]. Like Tunget et al. [1], we
found no association between ingested doses and the occurrence
and severity of symptoms. On the contrary, we found that
children could develop symptoms after intake of very small
LT doses (300 mcg).
The literature review identified two cases in children with
serious outcome (seizures) after the ingestion of 3600 mcg [8]
and 18,000 mcg LT [7]. Although there were many confound-
ing factors, these cases indicate – together with our own find-
ings – that children’s response to LT poisoning is highly
variable.
Regulatory biochemical mechanisms might be the reason
why even large doses of LT ingestion lead to mild toxicity.
There is evidence to suggest that the body responds to large

© 2015 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
 LEVOTHYROXINE POISONING 283

Table 3.
Levothyroxine cases and case series in children 1970–2010.
Age, years LT dose, mcg
Reference n (range) (range) Symptoms Author’s conclusions
Funderburk et al. 1970 1 3 13200 Fever, loose stool, tachycardia Large dose of thyroxine ingestion resulting
mild toxicity.
Gerard et al. 1972 2 2–3 – Fever, agitation, tachycardia (SVT) Children’s reactions to thyroid hormone
poisoning are unpredictable.
Tenenbein et al. 1981 9 1.75–15 1800–30000 2 developed mild symptoms Benign course.
Litovitz et al. 1984 78 <12 <500–16000 4 developed symptoms (fever, lethargy, Symptoms unlikely to be severe or
irritability, diarrhoea, vomiting, life–threatening.
tachycardia(SVT), abdominal pain)
Lehrner et al. 1984 7 1.3–3.3 3600–13200 3 developed symptoms (loose stool, Multiple control mechanism maintain
tachycardia, fever, vomiting, euthyroid status in spite of elevated serum
irritability, mydriasis) levels of thyroid hormones.
Kulig et al. 1985 1 2.5 18000 2 times grand mal seizure with postictal Severity of toxicity following overdose with
lethargy, irritability, tachycardia, levothyroxine varies widely.
tremulous, diaphoretic, diarrhoea
Roesch et al. 1985 1 1.83 5700 Tachycardia, mild hypertension Despite extremely high thyroxine levels on
admission, the patients’ symptoms
were mild.
Golightly et al. 1987 41 1–5 – 11 developed symptoms (tachycardia, Generally mild effects of accidental
hyperactivity, fever, vomiting, levothyroxine ingestions in children and
diarrhoea, diaphoresis, flushing) often unrelated to either estimated
amounts of hormone consumed or serum
thyroxine levels.
Gorman et al. 1988 1 1 12000 Tachycardia (SVT), loose stool, Rarely leads to clinical toxicity.
diaphoresis
Mandel et al. 1989 1 2.42 18000 Irritability, vomiting, tremor, After massive acute ingestions of
tachycardia levothyroxine, children’s symptoms are
generally mild.
Lewander et al. 1989 15 1–4.08 1500–8800 3 developed fever, tachycardia, agitation Although tolerant, children are not immune
to the development of moderate to severe
toxicity.
Berkner et al. 1990 2 2.5–3 – Both developed tachycardia, Two children successfully treated with
hypertension, fever sodium ipodate
Matthews 1993 1 14 3000 Initial dizziness Children are largely asymptomatic
Tunget et al. 1994 41 0.5–3.5 50–3750 8 developed symptoms (vomiting, Significant toxicity is not expected with
hyperactivity, diarrhoea, fever, rash, ingestions < 5000 mcg thyroxine
flushing, increased appetite, irritability,
insomnia)
Brown et al. 1997 1 2.5 Fever, tachycardia, agitation Iopanoic acid is a safe and effective drug in
the treatment of massive thyroid hormone
poisoning in children.
Shilo et al. 2002 1 13 9900 37.5°C, mild tremor of hands, mild Serious symptoms are less frequent in
anxiety children despite higher mean T4 and T3
levels than in adults. Serious
complications are not common.
Willgerodt et al. 2003 30 1.58–4.83 80–9500 8 developed tachycardia, hypertension Toxicity cannot be predicted solely on
initial blood concentrations of T4 and T3.
Toxicity depends on dose ingested.
Tsutaoka et al. 2005 1 3.5 3600 Tonic/clonic seizure, diarrhoea, Paediatric ingestions of < 5000 mcg
hyperactivity levothyroxine may result in serious
outcome
Ho et al. 2010 1 2.5 7600 Fever, tachycardia, desquamation of the Massive ingestion of levothyroxine in
palms and soles, hair loss, irritability children typically follows a benign course.
Majlesi 2010 1 2 6000 Hyperactivity, fever, vomiting, Potential serious sequelae after large
diarrhoea, irritability, tachycardia, mild levothyroxine ingestions.
tremulousness, irritability, lethargy

LT doses with the production of biologically inactive reverse proteins [22], and this might be another reason why ingested
triiodothyronine (rT3) to maintain an euthyroid state [3,5,21]. thyroid hormones prevent toxicity from developing.
Theoretically, rT3 acts as competitive inhibitor at receptor site We found that adults were more prone to develop symp-
and prevents LT toxicity [22]. LT also binds tightly to plasma toms. This is supported by other studies and can probably be

© 2015 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
284 BIRGITTE NYGAARD ET AL.
explained by existing underlying comorbidity including renal,
hepatic or cardiac disease that predisposes to develop severe
adverse reactions [9,10,23], or simply the fact that adults were
more prone to ingest other drugs alongside with their LT over-
dose. In our data, 45 adults co-ingested other drugs compared
to 8 children. Unfortunately, our data do not allow us to dis-
tinguish between these risk factors. These outcomes could,
however, be confounded by chronic LT poisoning (exogenous
hyperthyroidism) and/or an undiagnosed thyroid disease disre-
garding that chronic LT poisoning might be more severe than
acute poisoning. Indeed, some studies found a strong associa-
tion between endogenous hyperthyroidism and mortality
among adults [13,14], indicating that the regulatory biochemi-
cal mechanisms which maintains an euthyroid state in acute
LT poisoning is dysfunctional in chronic LT poisoning. In
GSK’s safety database, 71% of the children treated for hypo-
thyroidism were symptomatic after LT poisoning. This could
be due a chronic LT poisoning or the fact that long-term LT
use/hypothyroidism is a risk factor for the severity of acute
LT poisoning.
Only 16% of the patients presented symptoms by the time
DPIC was contacted. Out of the sample of patients followed
up, 43% described symptoms. The initial lack of symptoms
has also been described by other authors [3,4,7,23]. Symptoms
can be delayed for up to 6–11 days and do not correlate with
plasma levels of LT [18,24]. Clinical effects depend largely on
tissue concentrations of T3, and the delayed symptoms might
be indicative for the conversion of LT to T3 [25].
Late-onset symptoms cause challenges in terms of safe clini-
cal observation level. However, none of the late-onset symp-
toms reported at follow-up were severe. Furthermore, early GID
did not appear to influence the development of symptoms.
There are some obvious limitations in our study:
Firstly, the majority of results are based on retrospective
data, making it difficult to establish causality between ingested
LT dose and severity of symptoms. Secondly, we were only
able to follow up on a small percentage of patients. Therefore,
it cannot be excluded that our findings are influenced by
selection bias. The small number of responders, however,
expresses our difficulties in tracing them, and not the fact that
they did not want to participate. Therefore, we perceive this
group as a representative sample of the DPIC inquiries.
Thirdly, determining the time, amount ingested and symp-
toms is often difficult in children because of behavioural,
comprehension and speech-related challenges. When contact-
ing children who ingested LT up to years ago, some levels of
recall bias must exist.
Finally, the clinical effect of LT poisoning is increasing the
catecholamine activity leading to sympathomimetic clinical
manifestations, which makes it difficult to distinguish common
causes such as nervousness and anxiety which might result in
an overestimation of the clinical impact of LT poisoning.
In summary, the clinical outcome of LT poisoning is often
benign, and accidental intake of LT in moderate doses does
not require clinical monitoring or GID. Thus, defining a low-
est toxic level is difficult. However, during follow-up, we
found a large number of children describing late-onset
© 2015 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
LT-related symptoms. None of them were serious or needed
further treatment but should result in corresponding informa-
tion to the patient. We were not able to determine whether
adults were more sensitive to LT poisoning than children.
However, simultaneous intake of multiple concomitant drugs
and coexisting disease should be considered as risk factors.
Because of inadequate information at the DPIC database
concerning comorbidity (thyroid diagnosis), the frequency,
severity and impact of possible chronic LT poisoning and/or
hyperthyroidism/hypothyroidism were difficult to obtain.
Acknowledgements
We are grateful to nurse Lotte Lydeking for her assistance
in extracting data from the DPIC database, and we also thank
Aspen Pharma Trading Limited for the use of data.
Declaration of Interest
The authors report no conflict of interests. The authors alone
are responsible for the content and writing of this manuscript.
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© 2015 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)